A major problem in the treatment of cancer is the emergence of tumor cell resistance to chemotherapeutic agents and the subsequent patient relapse. These cancer victims may fail to respond to any antitumor agent since these tumor cells tend to exhibit clinical resistance to many drugs. This phenomenon is termed multidrug-resistance (MDR). MDR is associated with certain alterations in tumor cells, including an over-expression of a certain high molecular weight membrane glycoprotein and a decrease in the ability of the tumor cell to accumulate and retain chemotherapeutic agents.
Drugs of proven antitumor chemotherapeutic value to which multidrug-resistance has been observed include vinblastine, vincristine, etoposide, teniposide, doxorubicin (adriamycin), daunorubicin, plicamycin (mithramycin) and actinomycin D. Many tumors are intrinsically multidrug-resistant (e.g. adenocarcinomas of the colon and kidney) while other tumors acquire multidrug-resistance during therapy (e.g. neuroblastomas and childhood leukemias).
Agents are available which can restore drug sensitivity to some MDR tumor cells. Among these agents known to possess this property are calcium transport blockers (e.g. verapamil) and calmodulin inhibitors (e.g. trifluoperazine). Clinical use of these compounds has been limited by their extremely toxic side effects [Twentyman, P. R. et al., Int. J. Radiat. Oncol. Biol. Phys. 12: 1355 (1986)].
Cyclosporin A (CsA), a member of the family of immunosuppressive cyclosporins, has also been shown to have the ability to reverse the resistance of tumor cells to certain antitumor chemotherapeutic agents, both in vitro and in vivo [Slater, L. et al., Proc. Am. Assoc. Cancer Res. 27, 392 (1982)]. The mechanism by which cyclosporin A modulates multidrug-resistance is not understood. However, during clinical trials, significant benefit has been observed when cyclosporin A was used in conjunction with antitumor chemotherapeutic agents in treating patients with multidrug-resistant tumors. Due to the success of cyclosporin A in sensitizing multidrug-resistant tumor cells, it is expected that the administration of cyclosporin A prior to the emergence of multidrug-resistant tumor cells would prevent their subsequent emergence. Generally, cyclosporins are not directly cytotoxic or myelotoxic.
Unfortunately, immunosuppressive cyclosporins, including CsA, are highly nephrotoxic. In addition to its nephrotoxicity, CsA is known to have the following additional negative side effects:
1) abnormal liver function; PA0 2) hirsutism; PA0 3) gum hypertrophy; PA0 4) tremor; PA0 5) hyperaesthesia; PA0 6) gastrointestinal discomfort; PA0 7) neurotoxicity; and PA0 8) hypertension.
It is extremely undesirable to further compromise the health of a cancer victim by administering additional toxic drugs.
CsA is the drug of choice for preventing organ transplant rejection, and is also beneficial in treating autoimmune diseases, such as type 1 diabetes, multiple sclerosis, uveitis and rheumatoid arthritis. Despite these advantages, broader clinical application of CsA has been hampered by its severe nephrotoxicity (as well as other major organ toxicity) within the standard dose range of between 5 mg and 20 mg per kilogram per day.
The cyclosporins are a family of immunosuppressive compounds isolated from fermentation broths of various fungal species, including Tolypocladium inflatum and Cylindrocarpon lucidum.
The generic structure of the class of cyclosporins has been established as a cyclic peptide of formula I which contains 11 amino acids. ##STR1## For example, cyclosporin A of formula II contains seven N-methylated amino acids and a novel "C-9 amino acid" at position 1, designated as (4R)-4-[(E)-2-butenyl]-4,N-dimethyl-L-threonine(MeBmt). This novel amino acid is located in what is referred to as position 1 and has been found to be crucial for the immunosuppressive activity of cyclosporin A. ##STR2## Unless specified, the amino acid configuration is L.
The present invention describes a use for cyclosporin analogs that are effective in increasing the sensitivity of tumor cells resistant to anticancer chemotherapeutic agents, such as doxorubicin (DOX). This class of cyclosporin analogs is obtained by substituting the MeLeu residue at the 6-position of CsA with a MeAla or MeAbu residue. As evaluated in an in vivo mouse model, the cyclosporin analogs of this invention did not exhibit any nephrotoxicity. Furthermore, these compounds are non-immunosuppressive. The compounds described herein are also capable of enhancing the sensitivity of multidrug-resistant cells and, given their lack of nephrotoxicity, as measured in an in vivo mouse model, are expected to find broader clinical application than cyclosporin A itself. These compounds have the effect, as described herein, of reducing the resistance of MDR tumor cells, and potentiating the sensitivity of cells susceptible to antitumor agents such as DOX. Furthermore, since these cyclosporin analogs maintain the MDR-modulatory properties of cyclosporin A, it is expected that they possess all other MDR-related benefits of cyclosporin A treatment. Given their lack of nephrotoxicity these compounds are expected to have broad clinical application and may play a significant role in fighting cancer.